This invention relates to tropane analogs of cocaine and their use as inhibitors of monoamine reuptake.
Cocaine dependence is a problem of national significance. To date no cocaine pharmacotherapy has been reported. Cocaine is a potent stimulant of the mammalian central nervous system. Its reinforcing properties and stimulant effects are associated with its propensity to bind to monoamine transporters, particularly the dopamine transporter (DAT). (Kennedy, L. T. and I. Hanbauer (1983), J. Neurochem. 34: 1137-1144; Kuhar, M. J., M. C. Ritz and J. W. Boja (1991), Trends Neurosci. 14: 299-302; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K., J. B. Kamien, M. Fahey, D. Canfield, et al. (1990), Pharmacol Biochem. Behav. 35: 949-953; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Ritz, M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987), Science 237: 1219-1223; Schoemaker, H., C. Pimoule, S. Arbilla, B. Scatton, F. Javoy-Agid and S. Z. Langer (1985), Naunyn-Schmiedeberg""s Arch. Pharmacol. 329: 227-235.) It also binds with substantial potency to serotonin transporters (SERT) and norepinephrine transporters.
Structure activity relationship (SAR) studies have largely focused on a series of cocaine analogs. Among the more potent of these congeners at 3H-cocaine binding sites in striatum (Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129) is (1R)-3xcex2-(4-fluorophenyl)tropane-2xcex2-carboxylic acid methyl ester, (WIN35,428 or CFT) (Kaufman, M. J. and B. K. Madras (1992), Synapse 12: 99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141) reported in 1973 (Clarke, R. L., S. J. Daum, A. J. Gambino, M. D. Aceto, et al. (1973), J. Med. Chem. 16: 1260-1267). This compound was subsequently radiolabeled to provide a selective probe for the DAT in primate brain. (Canfield, D. R., R. D. Spealman, M. J. Kaufman and B. K. Madras (1990), Synapse 6: 189-195; Kaufman, M. J. and B. K. Madras (1991), Synapse 9: 43-49; Kaufman, M. J., R. D. Spealman and B. K. Madras (1991), Synapse 9: 177-187.)
Among the most potent tropane inhibitors of monoamine binding sites in striatum are 3xcex2-{4-(1-methylethenyl)phenyl}-2xcex2-propanoyl-8-azabicyclo(3.2.1)octane, (Bennett, B. A., C. H. Wichems, C. K. Hollingsworth, H. M. L. Davies, C. Thornley, T. Sexton and S. R. Childers (1995), J. Pharm. Exp. Ther. 272: 1176-1186; Davies, H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T. Sexton and S. R. Childers (1996), J. Med. Chem. 39: 2554-2558) (1R)-RTI55 (xcex2CIT), (Boja 1991; Boja, J. W., A. Patel, F. I. Carroll, M. A. Rahman, et al. (1991), Eur. J. Pharmacol. 194: 133-134; Neumeyer, J. L., S. Wang, R. A. Milius, R. M. Baldwin, et al. (1991), J. Med. Chem. 34: 3144-3146) (1R)-RTI121, (Carroll, F. I., A. H. Lewin, J. W. Boja and M. J. Kuhar (1992), J. Med. Chem. 35: 969-981.) and (1R)-3xcex2-(3,4-dichlorophenyl)-tropane-2xcex2-carboxylic acid methyl ester (O-401), (Carroll, F. I., M. A. Kuzemko and Y. Gao (1992), Med. Chem Res. 1: 382-387; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R. Elmaleh and B. K. Madras (1993), J. Med. Chem. 36: 855-862).
SAR studies of the binding of these agents and their effects on monoamine transporter function have been reported. (Blough, B. E., P. Abraham, A. H. Lewin, M. J. Kuhar, J. W. Boja and F. I. Carroll (1996), J. Med. Chem. 39: 4027-4035; Carroll, F. I., P. Kotian, A. Dehghani, J. L. Gray, et al. (1995), J. Med. Chem. 38: 379-388; Carroll, F. I., A. H. Lewin, J. W. Boja and M. J. Kuhar (1992),y J. Med. Chem. 35: 969-981; Carroll, F. I., S. W. Mascarella, M. A. Kuzemko, Y. Gao, et al. (1994), J. Med. Chem. 37: 2865-2873; Chen, Z., S. Izenwasser, J. L. Katz, N. Zhu, C. L. Klein and M. L. Trudell (1996), J. Med. Chem. 39: 4744-4749; Davies, H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T. Sexton and S. R. Childers (1996), J. Med. Chem. 39: 2554-2558; Davies, H. M. L., Z.-Q. Peng and J. H. Houser (1994), Tetrahedron Lett. 48: 8939-8942; Davies, H. M. L., E. Saikali, T. Sexton and S. R. Childers (1993), Eur. J. Pharmacol. Mol. Pharm. 244: 93-97; Holmquist, C. R., K. I. Keverline-Frantz, P. Abraham, J. W. Boja, M. J. Kuhar and F. I. Carroll (1996), J. Med. Chem 39: 4139-4141; Kozikowski, A. P., G. L. Araldi and R. G. Ball (1997), J. Org. Chem. 62: 503-509; Kozikowski, A. P., M. Roberti, L. Xiang, J. S. Bergmann, P. M. Callahan, K. A. Cunningham and K. M. Johnson (1992), J. Med. Chem. 35: 4764-4766; Kozikowski, A. P., D. Simoni, S. Manfredini, M. Roberti and J. Stoelwinder (1996), Tetrahedron Lett. 37: 5333-5336; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R. Elmaleh and B. K. Madras (1993), J. Med. Chem. 36: 855-862; Meltzer, P. C., A. Y. Liang and B. K. Madras (1994), J. Med. Chem. 37: 2001-2010; Meltzer, P. C., A. Y. Liang and B. K. Madras (1996), J. Med. Chem. 39: 371-379; Newman, A. H., A. C. Allen, S. Izenwasser and J. L. Katz (1994), J. Med Chem. 37: 2258-2261; Newman, A. H., R. H. Kline, A. C. Allen, S. Izenwasser, C. George and J. L. Katz (1995), J. Med. Chem. 38: 3933-3940; Shreekrishna, V. K., S. Izenwasser, J. L. Katz, C. L. Klein, N. Zhu and M. L. Trudell (1994), J. Med. Chem. 37: 3875-3877; Simoni, D., J. Stoelwinder, A. P. Kozikowski, K. M. Johnson, J. S. Bergmann and R. G. Ball (1993), J. Med. Chem. 36: 3975-3977.)
Binding of cocaine and its tropane analogs to monoamine transporters is stereoselective. As example (1R)-(xe2x88x92)-cocaine binds at the dopamine transporter about 200-fold more potently than the unnatural isomer, (1S)-(+)-cocaine. (Kaufman, M. J. and B. K. Madras (1992), Synapse 12: 99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K., R. D. Spealman, M. A. Fahey, J. L. Neumeyer, J. K. Saha and R. A. Milius (1989), Mol. Pharmacol. 36: 518-524; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Ritz, M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987), Science 237: 1219-1223.)
Also, only the R-enantiomers of cocaine have been found active in a variety of biological and neurochemical measures. (Clarke, R. L., S. J. Daum, A. J. Gambino, M. D. Aceto, et al. (1973), J. Med. Chem. 16: 1260-1267; Kaufman, M. J. and B. K. Madras (1992), Synapse 12: 99-111; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K., R. D. Spealman, M. A. Fahey, J. L. Neumeyer, J. K. Saha and R. A. Milius (1989), Mol. Pharmacol. 36: 518-524; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Ritz, M. C., R. J. Lamb, S. R. Goldberg and M. J. Kuhar (1987), Science 237: 1219-1223; Sershen, H., M. E. A. Reith and A. Lajtha (1980), Neuropharmacology 19: 1145-1148; Sershen, H., M. E. A. Reith and A. Lajtha (1982), Neuropharmacology 21: 469-474; Spealman, R. D., R. T. Kelleher and S. R. Goldberg (1983), J. Pharmacol. Exp. Ther. 225: 509-513.) Parallel stereoselective behavioral effects have also been observed. (Bergman, J., B. K. Madras, S. E. Johnson and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 150-155; Heikkila, R. E., L. Manzino and F. S. Cabbat (1981), Subst. Alcohol Actions/Misuse 2: 115-121; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129; Spealman, R. D., R. T. Kelleher and S. R. Goldberg (1983), J. Pharmacol. Exp. Ther. 225: 509-513; Wang, S., Y. Gai, M. Laruelle, R. M. Baldwin, B. E. Scanlet, R. B. Innis and J. L. Neumeyer (1993), J. Med. Chem. 36: 1914-1917.) For example, in primates and rodents the stimulating and reinforcing properties of the (xe2x88x92)-enantiomer of cocaine or its 3-aryltropane analogs were considerably greater than for the (+)-enantiomers.
Although SAR studies of cocaine and its 3-aryltropane analogs have offered insight into their mode of binding to monoamine transporters, a comprehensive picture of the binding interaction at the molecular level has not emerged. SAR studies on the classical tropane analogs (Carroll, F. I., Y. Gao, M. A. Rahman, P. Abraham, et al. (1991), J. Med. Chem. 34: 2719-2725; Carroll, F. I., S. W. Mascarella, M. A. Kuzemko, Y. Gao, et al. (1994), J. Med. Chem. 37: 2865-2873; Madras, B. K., M. A. Fahey, J. Bergman, D. R. Canfield and R. D. Spealman (1989), J. Pharmacol. Exp. Ther. 251: 131-141; Madras, B. K., R. D. Spealman, M. A. Fahey, J. L. Neumeyer, J. K. Saha and R. A. Milius (1989), Mol. Pharmacol. 36: 518-524; Meltzer, P. C., A. Y. Liang, A.-L. Brownell, D. R. Elmaleh and B. K. Madras (1993), J. Med. Chem. 36: 855-862; Reith, M. E. A., B. E. Meisler, H. Sershen and A. Lajtha (1986), Biochem. Pharmacol. 35: 1123-1129) appeared to provide a consistent model for this interaction with the DAT, however, subsequent studies revealed inconsistencies. (Carroll, F. I., P. Kotian, A. Dehghani, J. L. Gray, et al. (1995), J. Med. Chem. 38: 379-388; Chen, Z., S. Izenwasser, J. L. Katz, N. Zhu, C. L. Klein and M. L. Trudell (1996), J. Med. Chem. 39: 4744-4749; Davies, H. M. L., L. A. Kuhn, C. Thornley, J. J. Matasi, T. Sexton and S. R. Childers (1996), J. Med. Chem. 39: 2554-2558; Kozikowski, A. P., G. L. Araldi and R. G. Ball (1997), J. Org. Chem. 62: 503-509; Meltzer, P. C., A. Y. Liang and B. K. Madras (1994), J. Med. Chem. 37: 2001-2010; Meltzer, P. C., A. Y. Liang and B. K. Madras (1996), J. Med. Chem. 39: 371-379.)
Carroll had proposed (Boja, J. W., R. M. McNeill, A. Lewin, P. Abraham, F. I. Carroll and M. J. Kuhar (1992), Mol. Neurosci. 3: 984-986; Carroll, F. I., P. Abraham, A. Lewin, K. A. Parham, J. W. Boja and M. J. Kuhar (1992), J. Med. Chem. 35: 2497-2500; Carroll, F. I., Y. Gao, M. A. Rahman, P. Abraham, et al. (1991), J. Med. Chem. 34: 2719-2725; Carroll, F. I., M. A. Kuzemko and Y. Gao (1992), Med. Chem Res. 1: 382-387) four molecular requirements for binding of cocaine and its tropane analogs at the DAT: a 2xcex2-carboxy ester, a basic nitrogen capable of protonation at physiological pH, the R-configuration of the tropane and a 3xcex2-aromatic ring at C3. However, Davies (Davies, H. M. L., E. Saikali, T. Sexton and S. R. Childers (1993), Eur. J. Pharmacol. Mol. Pharm. 244: 93-97) later reported that introduction of 2xcex2-ketones did not reduce potency. Kozikowski questioned the role of hydrogen bonding at the C2 site because introduction of unsaturated and saturated alkyl groups (Kozikowski, A. P., M. Roberti, K. M. Johnson, J. S. Bergmann and R. G. Ball (1993), Bioorg. Med. Chem. Lett. 3: 1327-1332; Kozikowski, A. P., M. Roberti, L. Xiang, J. S. Bergmann, P. M. Callahan, K. A. Cunningham and K. M. Johnson (1992), J. Med. Chem. 35: 4764-4766) did not diminish binding. Further, the ionic bond between a protonated amine (at physiologically pH) and the presumed (Kitayama, S., S. Shimada, H. Xu, L. Markham, D. H. Donovan and G. R. Uhl (1993), Proc. Natl. Acad. Sci. U.S.A. 89: 7782-7785) aspartate residue on the DAT was questioned because reduction of nitrogen nucleophilicity (Kozikowski, A. P., M. K. E. Saiah, J. S. Bergmann and K. M. Johnson (1994), J. Med. Chem. 37(37): 3440-3442) by introduction of N-sulfones did not reduce binding potency.
It also has been reported (Madras, B. K., J. B. Kamien, M. Fahey, D. Canfield, et al. (1996), Pharmacol Biochem. Behav. 35: 949-953) that introduction of an alkyl or allyl group did not eliminate binding potency. An N-iodoallyl group on the tropane has provided potent and selective ligands for the DAT, and altropane is currently being developed as a SPECT imaging agent (Elmaleh, D. R., B. K. Madras, T. M. Shoup, C. Byon, et al. (1995), J. Nucl. Chem., 37 1197-1202 (1966); Fischman, A. J., A. A. Bonab, J. W. Babich, N. M. Alpert, et al. (1996), Neuroscience-Net 1, 00010, (1997). A 99mtechnetium labeled compound, technepine, which binds potently and selectively to the DAT and provides excellent in vivo SPECT images has been reported. (Madras, B. K., A. G. Jones, A. Mahmood, R. E. Zimmerman, et al. (1996), Synapse 22: 239-246.) (Meltzer, P. C., Blundell, P., Jones, A. G., Mahmood, A., Garada, B. et al., J. Med. Chem., 40, 1835-1844, (1997). 2-Carbomethoxy-3-(bis(4-fluorophenyl)methoxy)tropanes have been reported (Meltzer, P. C., A. Y. Liang and B. K. Madras (1994), J. Med. Chem. 37: 2001-2010). The S-enantiomer, (S)-(+)-2xcex2-carbomethoxy-3xcex1-(bis(4-fluorophenyl)methoxy)tropane (Difluoropine) was considerably more potent (IC50: 10.9 nM) and selective (DAT v. SERT: 324) than any of the other seven isomers, including the R-enantiomers.
Drug therapies for cocaine abuse are needed. Also, there is a need for protective agents for neurodegenerative diseases such as Parkinson""s disease and Alzheimer""s disease as well as therapeutic agents for dopamine related dysfunction such as Attention Deficit Disorder. Compounds that inhibit monoamine reuptake in the mammalian system are sought to provide such therapies.
Inhibition of 5-hydroxytryptamine reuptake has an effect on diseases mediated by 5HT receptors. Compounds that provide such inhibition can be useful, for example, as therapeutic anti-depressants.
Cocaine recognition sites are localized on monoamine transporters such as, for example, the dopamine transporter (DAT) and serotonin transporter (SERT). These transporters are localized, in turn, on monoamine nerve terminals. Compounds that bind to these sites can be useful as (i) probes for neuro-degenerative diseases (e.g., Parkinson""s disease), (ii) therapeutic drugs for neurodegenerative diseases (e.g., Parkinson""s and Alzheimer""s disease), (iii) therapeutic drugs for dopamine dysfunction (e.g., Attention Deficit Disorder), (iv) treatment of psychiatric dysfunction (e.g., depression) and (v) treatment of clinical dysfunction (e.g., migraine).
The compounds of this invention are new tropane analogs that bind to monoamine transporters. Thus, the present invention provides tropane analogs having one of the following formula: 
wherein:
R1=COOCH3, COR3, lower alkyl, lower alkenyl, lower alkynyl, CONHR4, or COR6;
R2=is a 6xcex1, 6xcex2, 7xcex1 or 7xcex2 substituent, which can be selected from OH, OR3, F, Cl, Br, and NHR3;
X=NR3, CH2, CHY, CYY1, CO, O, S; SO, SO2, NSO2R3, or C=CX1Y with the N, C, O or S atom being a member of the ring;
X1=NR3, CH2, CHY, CYY1 CO, O, S; SO, SO2, or NSO2R3;
R3=H, (CH2)nC6H4Y, C6H4Y, CHCH2, lower alkyl, lower alkenyl or lower alkynyl;
Y and Y1=H, Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)nCH3, COCH3, or C(CH3)3;
R4=CH3, CH2CH3, or CH3SO2;
R6=morpholinyl or piperidinyl;
Ar=phenyl-R5, naphthyl-R5, anthracenyl-R5, phenanthrenyl-R5, or diphenylmethoxy-R5;
R5=Br, Cl, I, F, OH, OCH3, CF3, NO2, NH2, CN, NHCOCH3, N(CH3)2, (CH2)nCH3, COCH3, C(CH3)3 where n=0-6, 4-F, 4-Cl, 4-I, 2-F, 2-Cl, 2-I, 3-F, 3-Cl, 3-I, 3,4-diCl, 3,4-diOH, 3,4-dioAc, 3,4-diOCH3, 3-OH-4-Cl, 3-OH-4-F, 3-Cl-4-OH, 3-F-4-OH, lower alkyl, lower alkoxy, lower alkenyl, lower alkynyl, CO(lower alkyl), or CO(lower alkoxy);
R6=morpholinyl or piperidinyl;
m=0 or 1;
n=0, 1, 2, 3, 4 or 5; and
when X is an oxygen atom or contains a carbon atom as the ring member, R2 can be H;
except that when X=N, R1 is not COR6.
The substituents at the 2 and 3 position of the ring can be xcex1- or xcex2-. Although R1 is illustrated in the 2- position, it should be recognized that substitution at the 3- position is also included and the position is dependent on the numbering of the tropane ring. The compounds of the present invention can be racemic, pure R-enantiomers, or pure S-enantiomers. Thus, the structural formulas illustrated herein are intended to represent each enantiomer and diastereomer of the illustrated compound.
The compounds of the present invention can be radiolabelled, for example, to assay cocaine receptors. Certain preferred compounds of the present invention have a high selectivity for the DAT versus the SERT.
The present invention also provides pharmaceutical therapeutic compositions comprising the compounds formulated in a pharmaceutically acceptable carrier.
Further, the invention provides a method for inhibiting 5-hydroxytryptamine reuptake of a monoamine transporter by contacting the monoamine transporter with a 5-hydroxy-tryptamine reuptake inhibiting (5-HT inhibiting) amount of a compound of the present invention. Inhibition of 5-hydroxy-tryptamine reuptake of a monoamine transporter in a mammal is provided in accord with the present invention by administering to the mammal a 5-HT inhibiting amount of a compound of the present invention in a pharmaceutically acceptable carrier. Preferred monoamine transporters for the practice of the present invention include the dopamine transporter, the serotonin transporter and the norepinephrine transporter.
In a preferred embodiment, the invention also provides a method for inhibiting dopamine reuptake of a dopamine transporter by contacting the dopamine transporter with a dopamine reuptake inhibiting amount of a compound of the present invention. Inhibition of dopamine reuptake of a dopamine transporter in a mammal is provided in accord with the present invention by administering to the mammal a dopamine inhibiting amount of a compound of the present invention in a pharmaceutically acceptable carrier.
The term xe2x80x9clower alkylxe2x80x9d when used herein designates aliphatic saturated branched or straight chain hydrocarbon monovalent substituents containing from 1 to about 8 carbon atoms such as methyl, ethyl, isopropyl, n-propyl, n-butyl, (CH2)nCH3, C(CH3)3; etc., more preferably 1 to 4 carbons. The term xe2x80x9clower alkoxyxe2x80x9d designates lower alkoxy substituents containing from 1 to about 8 carbon atoms such as methoxy, ethoxy, isopropoxy, etc., more preferably 1 to 4 carbon atoms.
The term xe2x80x9clower alkenylxe2x80x9d when used herein designates aliphatic unsaturated branched or straight chain vinyl hydrocarbon substituents containing from 2 to about 8 carbon atoms such as allyl, etc., more preferably 2 to 4 carbons. The term xe2x80x9clower alkynylxe2x80x9d designates lower alkynyl substituents containing from 2 to about 8 carbon atoms, more preferably 2 to 4 carbon atoms such as, for example, propyne, butyne, etc.
The terms substituted lower alkyl, substituted lower alkoxy, substituted lower alkenyl and substituted lower alkynyl, when used herein, include corresponding alkyl, alkoxy, alkenyl or alkynyl groups substituted with halide, hydroxy, carboxylic acid, or carboxamide groups, etc. such as, for example, xe2x80x94CH2OH, xe2x80x94CH2CH2COOH, xe2x80x94CH2CONH2, xe2x80x94OCH2CH2OH, xe2x80x94OCH2COOH, xe2x80x94OCH2CH2CONH2. etc. As used herein, the terms lower alkyl, lower alkoxy, lower alkenyl and lower alkynyl are meant to include where practical substituted such groups as described above.
When X contains a carbon atom as the ring member, reference to X is sometimes made herein as a carbon group. Thus, when X is a carbon group, as that phrase is used herein, it means that a carbon atom is a ring member at the X position (i.e., the 8-position).